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Studies Confirm Brain Plaque Can Help Predict Alzheimer’s

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Studies Confirm Brain Plaque Can Help Predict Alzheimer’s

Postby Teezer » Wed May 20, 2015 12:21 pm

From www.nytimes.com

The largest analysis to date of amyloid plaques in people’s brains confirms that the presence of the substance can help predict who will develop Alzheimer’s and determine who has the disease.

Two linked studies, published Tuesday in JAMA, also support the central early role in Alzheimer’s of beta amyloid, the protein that creates plaques. Data from nearly 9,500 people on five continents shows that amyloid can appear 20 to 30 years before symptoms of dementia, that the vast majority of Alzheimer’s patients have amyloid and that the ApoE4 gene, known to increase Alzheimer’s risk, greatly accelerates amyloid accumulation.

The findings also confirm that amyloid screening, by PET scan or cerebral spinal fluid test, can help identify people for clinical trials of drugs to prevent Alzheimer’s. Such screening is increasingly used in research. Experts say previous trials of anti-amyloid drugs on people with dementia failed because their brains were already too damaged or because some patients, not screened for amyloid, may not have had Alzheimer’s.

The research showed the ApoE4 gene had a bigger effect than some people expected, Dr. Ossenkoppele said. Even when people had one copy of a rarer ApoE2 gene that protects against Alzheimer’s, they were still at high risk of having amyloid if they had the ApoE4 gene.

So, ApoE4 "accelerates amyloid accumulation," but having amyloid accumulation doesn't necessarily mean that you'd have AD to go along with it.
It's weird how I'm constantly surprised by the passage of time when it's literally the most predictable thing in the universe. -- xkcd

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Re: Studies Confirm Brain Plaque Can Help Predict Alzheimer’s

Postby Harrison » Thu May 21, 2015 2:01 pm

So, ApoE4 "accelerates amyloid accumulation," but having amyloid accumulation doesn't necessarily mean that you'd have AD to go along with it.


This is precisely the case. In general, amyloid accumulation is poorly predictive of cognitive decline in Alzheimer's disease. This is why, at the present time, Medicare will not reimburse for amyloid PET scans using Florbetapir. The Centers for Medicare & Medicaid Services (CMS), is spending $80 million to determine if there is any utility in Florbetapir PET scans. Since there is currently no treatment to slow the disease progression of Alzheimer's, the answer is almost inevitably no. In addition, the findings of amyloid plaques in the brains of perfectly healthy 90 year-olds has led to a re-evaluation of the amyloid cascade hypothesis.

My own, admittedly controversial, opinion is that amyloid plaques are like a skin rash. There are many different, unrelated ways to get similar looking rashes. To me that is why most of the anti-amyloid antibodies have failed. They were treating a rash irrespective of the cause (or worse a medication for removing scabs). It may be the case the apoE4 is much more likely to lead to amyloid plaques, but the cause of memory loss could be mitochondrial dysfunction for all we know.

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Re: Studies Confirm Brain Plaque Can Help Predict Alzheimer’s

Postby Stavia » Thu May 21, 2015 4:48 pm

Harrison I like your analogy. It fits in well with my current thoughts on multifactorial aetiology of AD.
Could you elaborate more please?

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Re: Studies Confirm Brain Plaque Can Help Predict Alzheimer’s

Postby Harrison » Fri May 22, 2015 11:29 am

You initially had me at a loss, as you are the first person to ask me to elaborate. :shock: Thanks for asking. It has forced me to think things through a little more and might lead to some interesting discussion.

We know that certain autosomal dominant mutations (APP/PS1) in the amyloid pathway lead to AD. Amyloid plaques in these individuals are likely a direct result of the their mutation and possibly may be the cause of disease pathology. ApoE4 is less efficient at clearing amyloid and may lead to greater deposition of amyloid. This, however, does not necessarily have to be the mechanism by which apoE4 leads to cognitive decline. Robert Mahley and colleagues are big on the toxic fragments / mitochondrial dysfunction hypothesis. Other believe it could be neurofibrillary tangles, glucose regulation, etc. Beyond that, there are clearly AD cases with ApoE3 individuals, who would have neither the autosomal mutations or apoE4. How do they get plaques and/or tangles and what leads to their cognitive decline? It's not going to be exactly the same as APP or apoE4. There may be three separate diseases that are all called Alzheimer's disease. That doesn't even go into the whole "mixed pathology" vs. "Pure AD" that is actually observed in autopsy.

I am a believer of the two-hit hypothesis for Alzheimer's disease, so I tend to think in those terms. APP/PS1 + aging are two clear hits. ApoE4 is a hit, but needs to be combined with some problem (lysosomal dysfunction, glucose dysregulation, compromised cardiovascular function, perhaps even viral infection like HSV-1). ApoE3 carriers may have two other hits. In this compromised brain, normal clearance mechanisms may not be working properly, getting to overtly similar gross pathology irrespective of the original cause. Because of this, removing plaque, as evidenced by the bapineuzumab and solenuzumab, is not a panacea. Some argue that patients were started too late, but I think that's just more of the goal post moving that commonly occurs in the amyloid field (like the oligomer hypothesis).

As I said in the previous post, the above is controversal thinking, but other than the Biogen drug data from a few months ago (which probably won't work for apoE4 carriers due to side effects), the amyloid hypothesis has little to show for itself after 20+ years and billions of dollars.

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Re: Studies Confirm Brain Plaque Can Help Predict Alzheimer’s

Postby Juliegee » Fri May 22, 2015 2:15 pm

Great post, Harrison. I suspect that your theories are much less controversial than you think. I see many in the AD community finally moving away from the amyloid hypothesis; although, as you point out, Biogen still holds promise.

Your two hit hypothesis very much falls in line with my current thinking. It also dovetails beautifully with Dr.Bredesen's multifactorial approach. My guess is that it may take more hits for E3s to succumb as they don't share our vulnerabilities.

Identifying one's "hits" and/or preventing them also provides multiple opportunities for intervention- very hopeful.

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Re: Studies Confirm Brain Plaque Can Help Predict Alzheimer’s

Postby Stavia » Fri May 22, 2015 2:18 pm

Harrison, thank you for explaining. You have given me lots to think about, and a two-hit or three-hit paradigm is very hopeful for us.

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Re: Studies Confirm Brain Plaque Can Help Predict Alzheimer’s

Postby Gilgamesh » Sat May 23, 2015 4:15 am

Hi, Harrison. Thanks for your thoughts.

I agree with Julie that your ideas might be less radical than you think. Myself, I lean towards thinking amyloid is more important than many here seem to believe, based partly on my communication with the Iceland-based researchers who discovered the massively protective APP variation (http://www.alzforum.org/news/research-news/protective-app-mutation-found-supports-amyloid-hypothesis). But this of course doesn't rule out the multiple hit idea.

GB

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Re: Studies Confirm Brain Plaque Can Help Predict Alzheimer’s

Postby Harrison » Tue May 26, 2015 1:12 pm

Thank you for the responses. The relative level of controversy probably depends on the audience. Anybody who posted on the Alzforum page that Gilgamesh linked would probably not be inclined to agree with me. I am somewhat skeptical of the Decode data in general (not just AD, but also schizophrenia) due to the very rare nature of the variants they identify. It's not clear to me how much of that research will replicate and/or generalize in a broader study. Many genetic linkages come and go, and the only one that really has withstood the test of time for sporadic AD is of course apoE4. One of the comments on Alzforum was quite skeptical of the interpretation of the Decode data, and of course I agree with it :) :

Rather, the hypothesis that best fits the current body of evidence in the AD field, including the work by Jonsson et al., is that Aβ is a key element of the brain’s adaptive response to stress. The idea of an adaptive response to stress in the brain, in the context of both aging and AD pathogenesis, has been put forward in various forms by scientists including George Perry, Mark Smith, Karl Herrup, and others (Stranahan et al., 2011; Stranahan and Mattson, 2012; Nunomura et al., 2001; Pappolla et al., 2002; Castellani et al., 2009; Herrup, 2010; Castello and Soriano, 2012). The idea is that failure of this adaptive response, or its chronic activation, is what leads to sporadic AD, instead of overproduction of Aβ itself. The nature of that stress in the brain is wide ranging, encompassing microglia activation, accumulation of reactive oxygen species, and cholesterol dysregulation, and the adaptive response it elicits involves regulation of APP through its cleavage products, including Aβ and sAPPα (Castello and Soriano, 2012; Stranahan and Mattson, 2012; Castellani et al., 2009).


Amyloid beta is by definition a part of Alzheimer's disease, but for me the jury is still out and it could be more of a downstream response than a cause.


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